Osteoarthritis is common problem causing joint disease. The cause of osteoarthritis is complicated, but increases in inflammatory enzymes and cytokines have been correlated with joint damage in early osteoarthritis (He et al, 2020; Attur et al, 2015). These inflammatory markers have become a target of potential therapies.

What is Alpha-2-Macroglobulin or A2M?

Alpha-2-macroglobulin (A2M), a naturally occurring molecule that is found in the blood serum. Previous studies have demonstrated A2M can bind to and neutralized these destructive catabolic enzymes (Crookston et al, 1994; Feige et al, 1996; Dzhugashvili et al, 2014; Demirag et al, 2004; Demirag et al, 2005). By neutralizing these destructive enzymes, it is thought that A2M may affect the breakdown of cartilage (LaMarre et al, 1991; Santos et al, 2016).

What is the proposed mechanism for A2M injections in osteoarthritis?

The overall mechanism of how A2M works remains unclear. In osteoarthritis, various inflammatory enzymes and cytokines have been correlated with joint damage after a joint injury (Attur et al, 2015; Anderson et al, 2011; Backus et al, 2011; Borrelli et al, 2003; Tochigi et al, 2011).

A2M is thought to inhibit the majority of these destructive catabolic enzymes and cytokines that cause inflammation and degrade cartilage (Claassen et al, 2011; Wang et al, 2014). In vitro and pre-clinical studies have demonstrated that by neutralizing these destructive enzymes, A2M has a broad ability to block catabolic cytokines and enzymes (Wollenberg et al, 1991; Borth et al, 1990) and may reduce catabolism‐associated cartilage damage (Wang et al, 2014; Mathew et al, 2015; Wang et al, 2014; Zhang et al, 2017).

How is alpha-2-macroglobulin obtained and made?

A2M injections are not the same as a platelet-rich plasma or PRP injection. In traditional PRP injections the A2M molecules are not concentrated.

In an A2M injection, the A2M proteins are concentrated. At your appointment, your blood will be drawn and spun in a centrifuge similar to a traditional PRP injection. For an A2M injection, an additional step is performed using a special device to filter the plasma and concentrate the A2M macromolecules. Once the concentrated, the solution of A2M can then be injected into the arthritic joint.

Who is a good candidate for A2M injections?

Osteoarthritis is a common disease. Current treatment options mainly provide symptom relief, but generally do not halt the progression of osteoarthritis. A2M has emerged as an orthobiologic procedure for osteoarthritis, and theoretically has been discussed by Sun et al as potentially being able to slow or halt the development of early cartilage damage into significant disease (Sun et al, 2023).

There is limited clinical data to guide patient selection and few studies have compared the use of A2M to other injectable treatments in osteoarthritis.

What is the clinical evidence for A2M injections?

Alpha-2-macroglobulin (A2M) is a naturally occurring macromolecule, but little clinical data exists on the use of injectable macromolecules for the management of osteoarthritis of the knee.

In one prospective randomized controlled trial performed at NYU, 75 patients were divided into 3 groups and given either a PRP, A2M or corticosteroid injection. Patients were followed for 12-weeks. At the final follow-up visit at 12-weeks after the injection, the A2M group had a statistically significant improvement in functional scores compared to the PRP and corticosteroid groups(-18.4 v -5.7 v -7.1, p =0.03), and the study demonstrates Alpha-2-Macroglobulin decreased arthritic symptoms more than traditional PRP and corticosteroid injections (Klein et al, 2020). The major limitation of this study is that it provided no long term data on how patients did after that final follow-up visit at 12-weeks.

References:

1. Anderson DD, Chubinskaya S, Guilak F, et al. Post‐traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res. 2011;29(6):802‐809.
2. Attur M, Krasnokutsky S, Statnikov A, et al. Low‐grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers. Arthritis Rheumatol. 2015;67(11):2905‐2915.
3. Backus JD, Furman BD, Swimmer T, et al. Cartilage viability and catabolism in the intact porcine knee following transarticular impact loading with and without articular fracture. J Orthop Res. 2011;29(4):501‐510.
4. Borrelli J Jr, Tinsley K, Ricci WM, Burns M, Karl IE, Hotchkiss R. Induction of chondrocyte apoptosis following impact load. J Orthop Trauma. 2003;17(9):635‐641.
5. Borth W, Scheer B, Urbansky A, Luger TA, Sottrup‐Jensen L. Binding of IL‐1 beta to alpha‐macroglobulins and release by thioredoxin. J Immunol. 1990;145(11):3747‐3754.
6. Claassen H, Schicht M, Brandt J, et al. C‐28/I2 and T/C‐28a2 chondrocytes as well as human primary articular chondrocytes express sex hormone and insulin receptors—useful cells in study of cartilage metabolism. Ann Anat. 2011;193(1):23‐29.
7. Crookston KP, Webb DJ, Wolf BB, Gonias SL. Classification of alpha 2‐macroglobulin‐cytokine interactions based on affinity of noncovalent association in solution under apparent equilibrium conditions. J Biol Chem. 1994;269(2):1533‐1540.
8. Demirag B, Sarisozen B, Durak K, Bilgen OF, Ozturk C. The effect of alpha‐2 macroglobulin on the healing of ruptured anterior cruciate ligament in rabbits. Connect Tissue Res. 2004;45(1):23‐27.
9. Demirag B, Sarisozen B, Ozer O, Kaplan T, Ozturk C. Enhancement of tendon‐bone healing of anterior cruciate ligament grafts by blockage of matrix metalloproteinases. J Bone Joint Surg Am. 2005;87(11):2401‐2410.
10. Dzhugashvili M, Luengo‐Gil G, García T, et al. Role of genetic polymorphisms in NFKB‐mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys. 2014;90(3):595‐602.
11. Feige JJ, Negoescu A, Keramidas M, Souchelnitskiy S, Chambaz EM. Alpha 2‐macroglobulin: a binding protein for transforming growth factor‐beta and various cytokines. Horm Res. 1996;45(3‐5):227‐232.
12. He Y, Li Z, Alexander PG, et al. Pathogenesis of osteoarthritis: risk factors, regulatory pathways in chondrocytes, and experimental models. Biology. 2020;9(8):194.
13. Klein D, Bloom D, Campbell K, Gonzalez-Lomas G, Alaia M, Strauss E, Jazrawi L, Thompson K. Alpha-2-Macroglobulin Not Significantly Better Than Regular PRP For Knee Arthritis Symptoms. Orthop J Sports Med. 2020 Jul 31;8(7 suppl6):2325967120S00454.
14. LaMarre J, Wollenberg GK, Gonias SL, Hayes MA. Cytokine binding and clearance properties of proteinase‐activated alpha 2‐macroglobulins. Lab Invest. 1991;65(1):3‐14.
15. Mathew DJ, NewsomEM, Guyton JM, TuggleCK, Geisert RD, LucyMC. Activation of the transcription factor nuclear factor‐kappa B in uterine luminal epithelial cells by interleukin 1 Beta 2: a novel interleukin 1 expressed by the elongating pig conceptus. Biol Reprod. 2015;92(4):107.
16. Santos AC, Correia CA, de Oliveira DC, Nogueira‐Pedro A, Borelli P, Fock RA. Intravenous glutamine administration modulates TNF‐α/IL‐10 ratio and attenuates NFkB phosphorylation in a protein malnutrition model. Inflammation. 2016;39(6):1883‐1891.
17. Sun C, Cao C, Zhao T, Guo H, Fleming BC, Owens B, Beveridge J,
    McAllister S, Wei L. A2M inhibits inflammatory mediators of chondrocytes
    by blocking IL-1β/NF-κB pathway. J Orthop Res. 2023 Jan;41(1):241-248.
18. Tochigi Y, Buckwalter JA, Martin JA, et al. Distribution and progression of chondrocyte damage in a whole‐organ model of human ankle intra‐articular fracture. J Bone Joint Surg Am. 2011;93(6):533‐539.
19. Wang S, Wei X, Zhou J, et al. Identification of alpha2‐macroglobulin as a master inhibitor of cartilage‐degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheumatol. 2014;66(7):1843‐1853.
20. Wollenberg GK, LaMarre J, Rosendal S, Gonias SL, Hayes MA. Binding of tumor necrosis factor alpha to activated forms of human plasma alpha 2 macroglobulin. Am J Pathol. 1991;138(2):265‐272.
21. Zhang Y, Wei X, Browning S, Scuderi G, Hanna LS, Wei L. Targeted designed variants of alpha‐2‐macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection. Arthritis Res Ther. 2017;19(1):175‐175.